PROJECT SUMMARY Neuropathic pain (NP) conditions affect up to 7-8% of the population, while the annual costs of treatment reach $40 billion in the US. Pain reduction is more difficult to achieve in NP since the mechanisms involved are not the same as the mechanisms of normal, nociceptive pain. Current therapeutic approaches offer limited pain relief and frequently produce side effects that outweigh the benefits. More effective and better tolerated NP treatments are urgently needed. Aptinyx is developing a new approach to addressing NP. The company has developed a novel class of non-toxic, orally bioavailable compounds that modulate the N-methyl D-aspartate receptor (NMDAR) within the glutamatergic system. The NMDAR is a major player in regulating synaptic plasticity, which is involved in the development and maintenance of NP. Aptinyx's NMDAR partial agonists presumably act to normalize NMDAR activity by their ability to act as agonists or antagonists. Our preliminary data show that the lead compound, JY-505,317, displays a robust dose-dependent analgesic effect in multiple models of NP, matching or surpassing that of current treatments. Furthermore, its activity is restricted to NP, producing no sedation, and having no effect on nociceptive pain. Initial pharmacological data show excellent safety and bioavailability of JY-505,317, making it an excellent candidate for further development. NMDAR partial agonists previously developed at Aptinyx that JY-505,317 is based on, are currently in clinical development for major depression. The goal of this direct-to-Phase II project is to complete the remaining pre-clinical studies required for JY- 505,317 to advance to human trials for NP. To this end the specific aims are: Aim 1. Evaluate dosing of JY-505,317 in Bennett model of NP. Aim 2. Develop analytical techniques and obtain GMP material of Drug Substance and Drug Product. Aim 3. Conduct 28-day general-toxicology studies in the rat and the dog under GLPs. Aim 4. Conduct pharmacokinetics, safety-pharmacology and genotoxicity studies under GLPs. The end product of the proposed Phase II project is a complete safety package that will be submitted to the FDA as a part of an IND that will allow JY-505,317 to enter clinical trials.